monophosphate-activated protein kinase (AMPK) is a heterotrimeric
serine-threonine kinase important as a metabolic sensor for intracellular ATP levels
and plays a key role in regulating cell survival and proliferation,
particularly when cells are exposed to hypoxia. AMPK is critical for lung
function, and abnormal AMPK signaling participates in many lung diseases.
Recent studies suggest that both inhibition and activation of AMPK are
preventive for the development of pulmonary arterial hypertension (PAH).
However, the molecular mechanisms by which inhibition or activation of AMPK
affects pulmonary hypertension (PH) appear to be distinct. Inhibition of AMPK
by compound C blocks hypoxia-induced autophagy and induces apoptosis in
pulmonary artery smooth muscle cells, leading to prevention of PAH; activation
of AMPK by metformin attenuates the PH phenotype induced by hypoxia by
regulating endothelial cell function. These seemingly opposing data on the
function of AMPK in PH can be partly explained by off-target and
compartment-specific effects of AMPK inhibitors and activators and the
differentiated expression of AMPK in various cell types and subcellular
locations. To elucidate the specific roles of AMPK in the pathogenesis of PAH,
it is important to study the role of AMPK in a tissue specific manner combining
genetic and biochemical approaches.